Project Summary Tumor and microenvironment constitute complex ecologies involving a multitude of stromal cells, immune cells, and in some cases coexisting microbes. A paradigmatic example of complex tumor-microenvironment interactions are peripheral T-cell lymphomas, aggressive and genetically complex tumors where tumor cells often constitute a minority cell population. Peripheral T-cell lymphomas are frequently associated with the presence of Epstein-Barr virus whose role in the disease remains largely uncharacterized. We have shown that the presence of specific macrophage populations and viral transcriptional programs are associated to survival. But, how do tumor and microenvironment coevolve and inform prognosis? Our project goal is to characterize the tumor- microenvironment interactions and coevolution in peripheral T-cell lymphomas using large collections of human transcriptomic data and longitudinal single-cell sequencing data from recently developed mouse models. We will develop an approach based on random matrix theory and topological data analysis for modelling the continuous aspect of tumor microenvironment evolution. We will further deploy our lab-developed methodology for in silico pathogen detection to study the interactions between the Epstein-Barr virus and peripheral T-cell lymphoma lymphomagenesis and progression. Successful completion of our goals will provide a general, experimentally validated strategy to uncover the dynamical nature of tumor-microenvironment interactions at the single-cell resolution in tumor types with complex stromal component. Additionally, our approach will help uncover new microenvironment driven targets supporting lymphoma cell growth, with potential therapeutic implications for the treatment of this deadly disease.